The invention relates to new arylglycinamide derivatives of general formula I 
and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
The abbreviations used in the specification and claims are explained as follows:
CDI=Carbonyldiimidazole
DCCI=Dicyclohexylcarbodiimide
HOBt=1-Hydroxybenzotriazole
THF=Tetrahydrofuran
DMF=Dimethylformamide
RT=Room temperature
DMAP=4-Dimethylaminopyridine
TBTU=O-Benzotriazolyl-tetramethyluroniumtetrafluoroborate
In order to show the formulae, a simplified representation is used. In the representation of the compounds all CH3-substituents are represented by a single bond, and for example the following formula 
represents 
The invention relates to new aryiglycinamide derivatives of general formula I 
or the pharmaceutically acceptable salts thereof,
wherein
Ar denotes unsubstituted or mono- to pentasubstituted phenyl, or unsubstituted or mono- or di-substituted naphthyl, [in which the substituents of the phenyl and naphthyl independently of each other denote halogen (F, Cl, Br, I), OH, (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR9R10 (wherein R9 and R10 independently of each other denote H, methyl or acetyl)] or Ar is phenyl""substituted by xe2x80x94OCH2Oxe2x80x94 or xe2x80x94O(CH2)2Oxe2x80x94;
R1 and R2 together with the N to which they are bound form a ring of the formula 
wherein
p is 2 or 3,
X denotes oxygen, N(CH2)nR6 or CR7R8, wherein
n is 0, 1 or 2,
R6 is (C3-7)cycloalkyl, phenyl or naphthyl, wherein the phenyl may be mono- to tri-substituted by halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF2 or NR15R16 (wherein R15 and R16 independently of each other denote H, methyl or acetyl);
R7 and R8 have one of the following meanings:
a) R7 and R8 represent H if R3 is unsubstituted or substituted phenyl,
b) R7 is phenyl, phenyl substituted by 1 to 3 substituents [wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3 or OCF3], piperidinyl, 1-methylpiperidinyl, 
xe2x80x83if R8 is H, xe2x80x94CONH2, xe2x80x94NHC(O)CH3, xe2x80x94N(CH3)C(O)CH3, CN 
xe2x80x83or xe2x80x94C(O)N((C1-3)alkyl)2 or
c) R7 and R8 together form the group 
R3 denotes H, (C1-4)alkyl, unsubstituted or mono- to tri-substituted phenyl, wherein the substituents independently of one another represent halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR17R18 (wherein R17 and R18 independently of one another denote H, methyl or acetyl);
R4 denotes phenyl(C1-4)alkyl or naphthyl(C1-4)alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and
R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, xe2x80x94CH2C(O)NH2, xe2x80x94OH or phenyl(C1-4)alkyl.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P-antagonism and also neurokinin A- or neurokinin B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases.
Compounds of general formula I may contain acid groups, chiefly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be obtained either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine or triethanolamine, etc.
The compounds according to. the invention may occur as racemates but may also be obtained as pure enantiomers, i.e. in (R)- or (S)-form. They may also occur as diastereoisomers or mixtures thereof.
The preferred compounds of general formula I are those wherein
R1 and R2 together with the N to which they are bound form a 6-membered ring of the formula 
wherein
X denotes N(CH2)nR6 or CR7R8,
wherein n, R6, R7 and R8 are defined as in claim 1.
Particular mention should be made of compounds of formula I wherein
X is N(CH2)nR6 wherein n is 0, 1 or 2 and R6 is (C3-7)cycloalkyl or phenyl, particularly those compounds wherein n is 0 and R6 is (C3-7)cycloalkyl, particularly those compounds wherein R6 is cyclobutyl or cyclohexyl.
Mention should also be made of compounds of formula I wherein
R7 and R8 have one of the following meanings:
a) R7 and R8 denote H when R3 is unsubstituted or substituted phenyl,
b) R7 is phenyl, piperidinyl 
xe2x80x83if R8 is H, xe2x80x94CONH2, xe2x80x94NHC(O)CH3, xe2x80x94N(CH3)C(O)CH3 or CN, or
c) R7 and R8 together form the group 
xe2x80x83particularly those wherein
R7 and R8 have one of the following meanings:
a) R7 and R8 denote H when R3 is unsubstituted or substituted phenyl,
b) R7 is phenyl, 
xe2x80x83when R8 is H, xe2x80x94CONH2 or CN, or
c) R7 and R8 together form the group 
The preferred compounds are those wherein
R7 denotes phenyl 
xe2x80x83and R8 is H or CN, particularly those wherein R7 is pyridino and R8 is H.
Of the compounds defined above, the preferred ones are those wherein
Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), OH, methyl, methoxy, CF3, OCF3 or dimethylamine] or Ar is phenyl substituted by xe2x80x94OCH2Oxe2x80x94, this group connecting positions 2 and 3 or 3 and 4 of the phenyl, particularly those wherein
Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br), methoxy or CF3] or Ar is phenyl substituted by xe2x80x94OCH2Oxe2x80x94, this group connecting positions 2 and 3 or 3 and 4 of the phenyl.
The preferred compounds are those wherein Ar is phenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl.
Of the compounds defined above, particular mention should be made of those wherein R3 is phenyl or preferably H.
Of the compounds defined above, mention should also be made of those wherein
R4 denotes phenyl(C1-3)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, the substituents independently of one another being halogen (F, Cl, Br, I), methyl, methoxy, CF3 or OCF3; and
R5 denotes H, (C1-3)alkyl, CH2COOH, xe2x80x94CH2C(O)NH2 or phenethyl,
particularly those compounds wherein
R4 is 
and R5 denotes H or CH3.
The following compounds are preferred: 
The term naphthyl used above includes both 1-naphthyl and 2-naphthyl.
Test results for compounds according to the invention:
The receptor affinity for the NK1-receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK1-receptors, measuring the displacement of 125I-labelled substance P. The Ki-values thus obtained demonstrate the efficacy of the compounds:
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have, in particular, NK1-antagonism, but also NK2- and NK3-antagonistic properties.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P-antagonism and also neurokinin A- or neurokinin B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases: treatment and prevention of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic bronchitis, emphysema, rhinitis or coughs, eye diseases such as conjunctivitis and iritis, skin diseases such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites and stings, neurodermitis, itching and postherpetic pain,
diseases of the gastrointestinal tract such as gastric and duodenal ulcers, ulcerative colitis, Crohn""s disease, irritable bowel, Hirschsprung""s disease;
diseases of the joints such as rheumatoid arthritis, reactive arthritis and Reiter""syndrome;
for treating diseases of the central nervous system such as dementia, Alzheimer""s disease, schizophrenia, psychosis, depression, headaches (e.g. migraine or tension headaches) and epilepsy;
for the treatment of tumours, collagenosis, dysfunction of the urinary tract, haemorrhoids, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion and pain of all kinds.
The invention therefore also relates to the use of the compounds according to the invention as remedies and pharmaceutical preparations which contain these compounds. They are preferably for use in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route or by inhalation, by transdermal route, if desired with the aid of iontophoresis or enhancers known from the literature, and by oral route.
For parenteral administration, the compounds of formula I or the physiologically acceptable salts thereof, optionally with conventional substances such as solubilisers, emulsifiers or other adjuvants, may be made into solutions, suspensions or emulsions. Suitable solvents include, for example, water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents.
In addition, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or by means of intranasal preparations.
The oral effectiveness of compounds of general formula I can be demonstrated using the following standard test:
Inhibition of the lowering of blood pressure caused by NK1 in anaesthetised guinea pigs.
Guinea pigs weighing 300-500 grams were anaesthetised with pentobarbital (50 mg/kg i.p.), intubated and mechanically ventilated with 10 ml of ambient air per kg of body weight at a rate of 60 breaths per minute. The blood pressure was measured in the blood flow through the carotid artery. In order to introduce substances intravenously, the jugular vein was cannulated.
By the intravenous administration of the NK1-agonist [xcex2Ala4, Sar9, Met(O2)11] SP(4-11) (0.2 xcexcmol/kg) a brief lowering of the blood pressure was triggered which was repeated at 10 minute intervals by repeatedly giving the NK1-agonist. 
The neurokinin-antagonist was then administered by intraduodenal route and at 10 minute intervals a lowering of blood pressure was induced by means of the NK1-agonist.
The inhibition of the lowering of blood pressure caused by the above-mentioned NK1-agonist was measured before and after treatment with the neurokinin-antagonist.
The compound of Example 5 yielded an ID50 of 1.4 mg/kg. (ID50 is the dose which inhibits the lowering of blood pressure caused by the NK1-agonist by 50%.)
The compounds according to the invention may be prepared by generally known methods.
The compounds may be prepared in various ways. The two commonest methods are shown in the following scheme: 
Method A. The carboxylic acid may be linked to the amine HN(R5)R4 in various ways. The usual methods are coupling methods such as those used in peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, CDI, etc., is added to the coupling partners in an approximately equivalent amount. Suitable solvents are DMF, THF, CH2Cl2, CHCl3, acetonitrile or other inert solvents or mixtures thereof. The appropriate temperature range is between xe2x88x9250xc2x0 C. and +120xc2x0 C., preferably between 0xc2x0 C. and 40xc2x0 C.
The carboxylic acid may also initially be converted by means of SOCl2, SO2Cl2, PCl3, PCl5 or PBr3 or mixtures thereof, by known methods, into the corresponding acid halide which is subsequently reacted with the amine HN(R5)R4 in an inert solvent such as CH2Cl2, THF or dioxane at temperatures between xe2x88x9250xc2x0 C. and +100xc2x0 C., typically between 0xc2x0 C. and 20xc2x0 C.
Another alternative is to convert the carboxylic acid initially into the alkylester, usually the methylester, by known methods and then to react this ester with the amine HN(R5)R4 in an inert solvent such as DMF, dioxane or THF. The reaction temperatures are between 20xc2x0 C. and 150xc2x0 C., typically between 50xc2x0 C. and 120xc2x0 C. The reaction may also be carried out in a pressurised container.
Process B. In this, the xcex1-halo-arylacetamide derivative obtained according to known procedures is reacted with the amine R1(R2)NH, thereby generating hydrogen halide. In order to mop up the cleaved (or excess) hydrogen halide, inorganic bases are used such as K2CO3, NaHCO3 or CaCO3, or organic bases may be used such as triethylamine, Hung base, pyridine or DMAP, or an excess of the amine R1(R2)NH may be used. DMF, THF, dioxane or other inert solvents are used. The temperature range for the reaction is from 0 to 100xc2x0 C., typically from 10 to 80xc2x0 C.
Process C. The compounds according to the invention in which R5 is not H may also be prepared as follows: first of all, the corresponding compound in which R5 is H is synthesised according to process A or B. Then N-alkylation is carried out as follows in order to introduce alkyl, cycloalkyl or CH2COOH. The compound according to the invention wherein R5 is H is deprotonated with an equivalent quantity of NaH, NaNH2, KOH, NaOCH3 or some other strong base. Anhydrous inert solvents such as THF, dioxane or diethylether are used. Then the corresponding alkylating agent is added slowly in the form of the corresponding halide, tosylate or mesylate. The reaction is carried out in the temperature range from xe2x88x9250xc2x0 C. to +100xc2x0 C., typically between 0xc2x0 C. and +50xc2x0 C. The method is described in detail in Example 33.